Factors associated with poor outcomes in patients with severe acute respiratory infections in Bahrain

Abstract Background Severe acute respiratory tract infection (SARI) is a major global health threat. This study aimed to examine risk factors associated with poor outcomes in patients with SARI. Methods All patients who met World Health Organization's (WHO) SARI case definition and were admitted to Salmaniya Medical Complex from January 2018 to December 2021 were included. Epidemiological and virological data were obtained and analyzed. Results Of 1159 patients with SARI included, 731 (63.1%) patients were below 50 years, and 357 (30.8%) tested positive for viral pathogens. The most prevalent virus was Flu‐A (n = 134, 37.5%), SARS‐CoV2 (n = 118, 33%), RSV (n = 51, 14.3%), Flu B (n = 49,13.7%), other viruses (n = 3, 0.8%), and combined infection (n = 2, 0.6%). Six hundred fifty‐eight (56.8%) patients had comorbidities, mainly diabetes (n = 284, 43%) and heart disease ( n = 217, 33%). 183 (16%) patients were admitted to ICU, 110 (9%) needed mechanical ventilation, and 80 (7%) patients died. The odds of ICU admission were higher for patients with hematological (OR 5.9, 95% CI 3.1–11.1) and lung diseases (OR 2.7, 95% CI 1.6–4.6). The odds of mechanical ventilation were higher among patients with lung disease (OR 3.1, 95% 1.7–5.5). The mortality odds were higher among patients above 50 (OR 2.4, 95% CI 1.4–4.1) and chronic kidney disease (OR 2.5, 95% CI 1.1–5.2). Conclusions Being 50 years or above or having kidney, lung, or heart diseases was associated with worse SARI outcomes. Efforts and actions in developing better strategies to vaccinate individuals at high risk and early diagnosis and treatment should help in reducing the burden of SARI.


| INTRODUCTION
Acute respiratory tract infections are one of the major global health threats. They have been the cause of more than one pandemic in the last century leading to the death of a large number of people. Back in 1918, the Spanish flu resulted in the death of around 50 million people, and in the 1950s and 60s, H2N2 (Asian flu) and H3N2 (Hong Kong flu) were estimated to cause the death of around 2 million people. [1][2][3] Globally, severe acute respiratory infections (SARI) are estimated to be the cause of death in about 19% of all children younger than 5 years. 4 In the United States alone, influenza viruses are predicted to be causing 12,000 to 61,000 deaths annually. 5 Globally, it was also estimated that 291,000 to 645,000 deaths were caused by influenza viruses each year. 6 In 1952, the influenza surveillance program was started by the World Health Organization (WHO). The aim of the influenza surveillance program is to reduce mortality and morbidity of the disease in the community by providing valuable information to the authorities for better interventions and control plans. In addition, it could be used to guide influenza vaccine production and detect emerging variants. Such programs are also important to prioritize intervention and give attention to high-risk patients, where such infections could lead to higher rates of mortality. 7 Many studies found that mortality was high among patients with SARI who were elderly or had associated comorbidities. [8][9][10] However, risk factors associated with poor outcomes in SARI patients are not well established. During the H1N1 pandemic, mortality was high even among younger age groups. 11 Accordingly, monitoring SARI in different age groups is essential to understand the spread of the disease in the community. 12 Moreover, there were no published studies that addressed SARI in the Kingdom of Bahrain. Therefore, this study was conducted with the main objective of identifying the risk factors associated with poor outcomes, including mortality, ICU admission, and mechanical ventilation among patients admitted with SARI in Bahrain.

| Study population
All patients that met the definition of SARI by the WHO and as adopted by SARI surveillance in Bahrain were included in the study.
Thus, patients admitted to the hospital due to acute respiratory tract infection, complaining of cough, and having a temperature of ≥38 C or a history of fever in the last 10 days were enrolled. 13

| Data collection
Data were collected and stored electronically in the WHO EMFLU database by an experienced public health specialist. Following data variables were collected as part of the surveillance: age, sex, area of residence, pre-existing medical conditions, antiviral medications prescribed, influenza vaccination status, history of travel, history of contact with a sick patient, place of admission, admission to ICU, mechanical ventilation requirement, and status upon discharge (death or alive).

| Specimen collection and testing
Influenza reverse transcription-polymerase chain reaction (RT-PCR) tests were performed for all the patients in the national influenza center in the public health laboratory to identify the causative agents.
COVID-19 PCR was also done during the coronavirus pandemic years 2020-2021. Integrated surveillance (SARS-CoV2, influenza and RSV) was conducted using nasopharyngeal swabs. Specimens were stored in a viral transport media and refrigerated until processing within a period of 24 h from the time of sampling. Laboratory processing and diagnosis of specimens were performed according to the WHO standards. 14

| Statistical analysis
Patients' data were first exported from the EMFLU database into Microsoft Excel and transferred to IBM Statistical Package for the Social Sciences (SPSS) software version 21 for statistical analysis.
Quantitative variables were reported as mean and standard deviations, whereas qualitative variables were described using counts and percentages to obtain the descriptive analysis. Categorical groups of variables were compared using the Chi-square test. Univariate analysis and odds ratios were also calculated. Factors associated with an increased risk of mechanical ventilation, ICU admission, or death were assessed using logistic regression. Significant factors found through univariate logistic regression and relevant factors from the literature were analyzed using a multivariate logistic regression model to adjust for confounders. To examine the individual impact of each comorbidity on the risk of mortality, we analyzed the data using the Chi-Square test, comparing patients with specific comorbidity with patients with no comorbidities (e.g., patients having diabetes compared with those without diabetes).

| Ethical approval
This study was conducted in accordance with the principles of the Helsinki Declaration, and it was ethically approved by the Health Research Committee in the Ministry of Health, Kingdom of Bahrain.
Each patient signed a written informed consent upon hospital admission, and the research team received the data anonymized from the influenza surveillance team.

| Patients' characteristics
During the study period, a total of 1159 patients were found to be enrolled in the SARI surveillance program. Most of the patients were males (n = 674, 58.2%) and below the age of 50 years (n = 731, 63.1%). The mean age was 40 ± 25 years. The rate of influenza vaccination among the patients was low (n = 25, 2.2%). None of the vaccinated patients tested positive for influenza. Only 130 (11.2%) patients received antiviral medications.

| Case fatality
The case fatality of SARI was 6.2% (80/1159). The mean age at death was 52 ± 26 years, and most were males (n = 44, 55%). Twenty-six (32.5%) deceased patients had a positive virological test. The most common pathogen identified among them was influenza A in 10 (12.5%) patients followed by COVID-19 in nine (11.3%) patients. Antiviral medications were given to 11 (13.8%) patients, and none of them had received the influenza vaccine in the season. Sixty-three (78.8%) patients had comorbidities, and 39 (48.8%) of them had more than one comorbidity. The most common was heart disease, 27 (33.8%), followed by diabetes in 26 (32.5%) patients (Table 1).
On logistic regression analysis, higher mortality was noted in patients older than 50 years (OR 3.   Odds ratios were not calculated for some variables due to low numbers.
a Other viruses and comorbidities were not specified or recorded other than the ones listed above, thus not included in the analysis.

| Logistic regression/multivariate analysis
This could be explained by the high prevalence of both diseases in the general population. 16,17 In Bahrain, the prevalence of diabetes and hypertension is high, at 15% and 33%, respectively. 18

| Laboratory results
All of the enrolled patients were tested for respiratory pathogens via RT-PCR of samples collected by nasopharyngeal swabs. However, only 30% had a causative agent detected. This was similar to findings in five Eastern Mediterranean countries, Vietnam, and Arizona. 8,9,12,19 In a multicentric European study, the causative agent's detection rate in SARI surveillance ranged from 2.1% to 100%. 10 The low yield of positive results could be due to the delay of collection of specimens, as it is recommended to be within 4 days from the onset of illnesses, or due to other respiratory pathogens not being tested for. 20

| ICU admission
The ICU admission rate in this study was lower (15.8%) than those reported by other studies, which ranged from 25% in Egypt to 40% in Arizona. 8,12,15,22 The lower rate of admission in Bahrain might be related to the lower age of patients with SARI compared with the study from Arizona.
Our study found that comorbidities increased the risk of ICU admission. Similar results were found in other studies in the Eastern Mediterranean region, the European region, and Chile. 9,10,15,22 In the European region study, further analysis found that chronic heart and lung diseases were linked to a higher risk of admission to the ICU. 10 Furthermore, patients with SARI were at higher risk of being admitted to ICU if they tested positive for influenza A. In this study,

(16.9%) of the ICU-admitted patients tested positive for influenza
A. Yet, findings in the literature were inconsistent; whereas some linked the detection of a causative agent with lower rates of admission, 8,12 others found no association between testing positive and ICU admissions. 9 However, one study found a higher risk of admission in influenza-positive patients, similar to our findings. 10

| Mechanical ventilation
Pneumonia is the commonest complication of influenza infections. 23 Susceptible patients may deteriorate to reach respiratory failure. 5 One hundred ten (9.5%) patients developed respiratory failure during their SARI episode, which required mechanical ventilation. This rate was lower than those in other surveillance programs, which ranged from 19% to 22%. 8,12,15 The majority of ventilated patients had chronic diseases (n = 76, 69%), and no viral agent was detected in 74 (67.3%) patients.
Although data on the risk factors resulting in a SARI patient requiring mechanical ventilation is scarce, our results were comparable to findings from a study conducted in our (EMR) region. 9 RSV infections were linked with a milder form of the disease in children with SARI 8 ; despite that, we found that it was associated with higher rates of ventilation when adults were infected.

| Case fatality
Eighty ( Higher rates of mortality were correlated with age above 50 years or having underlying diseases. Studies in the region found similar results; those aged above 50 years and having underlying diseases increased the odds of severe outcomes (indicated by death, ICU admission, or ventilation). 8,9 The study done in Europe, along with a globally conducted study, revealed similar results. 10,24 However, the study conducted in Chile found that age and comorbidities were not linked with higher mortality rates. 15 We found that an immunocompromised state and chronic lung, kidney, or heart diseases were all associated with higher mortality.
This is comparable to the European study findings. 10 Detecting a viral pathogen in our admitted patients was not associated with increased mortality. Likewise, many studies had similar findings. 8,9,15 However, a study conducted in Europe reported the influenza virus as a risk factor for mortality. 10 This may suggest that factors other than the causative agents, such as patient characteristics, age, and comorbidities, played a more significant role in the outcome of patients with SARI.

| Vaccination
The seasonal influenza vaccine remains the mainstay measure to decrease the burden of SARI by preventing influenza infections and lowering the need for ICU admission and mortality in infected patients. [25][26][27] In Bahrain, the influenza vaccine is recommended for all citizens, below the age of 5, above the age of 50, or having chronic diseases. 28

| Antiviral treatment
Studies found that prompt treatment of influenza infections with antiviral drugs decreases the risk of mortality and reduces hospital length of stay. [29][30][31][32] Furthermore, it is associated with lower hospitalization rates in high-risk patients. 33 Timely initiation of antiviral treatment is key, especially in high-risk groups. 29,31,34 Despite that, only 130 (11.2%) of our admitted patients received antiviral medication. In our sample, patients taking the antiviral medication were more likely to be admitted to the ICU or ventilated. As data about the time of initiation of treatment from the onset of symptoms was not available, we suspect that these findings were due to the administration of antivirals in critically ill patients, after the progression of the disease and in non-influenza patients.

| Limitation
The study used the SARI surveillance data, which helps to identify the limitations of the surveillance system. 35

ACKNOWLEDGMENTS
The authors gratefully acknowledge all medical staff working at the pediatric and medical departments at SMC, the public health laboratory personnel in the National Influenza Center, and the communicable disease surveillance group in the Public Health Directorate.

CONFLICT OF INTEREST STATEMENT
No financial or non-financial benefits have been received or will be received from any party directly or indirectly related to this article's subject.

DATA AVAILABILITY STATEMENT
Data will be made available on reasonable request.

ETHICS STATEMENT
This study was conducted in accordance with the principles of the